Human natural killer (NK) cells play an important role in physiological and pathological conditions. Their cytotoxic and noncytotoxic functions are mediated and regulated by signal transducing cell-surface structures such as Fc receptors (FcR) interacting with IgG. The FcgammaRIII, identified by anti-CD16 monoclonal antibodies (mAb) on most human NK cells, is considered to bind with low affinity only polymeric IgG (pIgG) but not IgG in monomeric form (mIgG) and to be the sole type of FcgammaR on NK cells. Contrary to these generally accepted opinions, there are several lines of evidence, including considerable collaborative studies, between the laboratories of Drs. A. Sulica and R. B. Herberman, showing that mIgG down-regulates human NK activity, an inhibition which is (i) triggered by interaction with FcgammaRIII and mediated by elevation of cyclic AMP; (ii) reversed by pretreatment with interferon gamma; (iii) induced also by IgG1 and IgG3 myeloma proteins as well as by synthetic peptide Y75, comprising the sequence Tyr407-Arg416 of IgG Cgamma3 domain. More recently reported data indicate that this novel mechanism for inhibition of NK cell activity can be triggered also by IgM and IgA molecules and appears to have a biological significance, in view of the decreased NK cell activity found in patients on IVIG therapy. Additional results document that the mIgG-fcgammaRIII interaction and the subsequent inhibition of NK cell activity are reduced by IgG1 anti- CD16 mAbs. Findings to be reported show that the anti-FcgammaRIII mAbs have direct NK regulatory effects which are dependent on both the NK cell donor and the isotype of IgG. Donor responsiveness to anti-CD16 regulation has correlated with responsiveness to the synthetic peptide Y75. Very recent evidence derived from molecular biologic, binding and functional studies, performed at the Pittsburgh Cancer Institute and the Victor Babes Institute, has elicited the presence of another type of FcgammaR on NK cells, namely the FcgammaRII (CD32+). Based on the background provided by studies carried out by us and by others, the proposed research project is that a minor subpopulation of mIgG molecules possess the cytophilic property which endows them with the ability to bind to FcgammaRIII and possibly FcgammaRII on NK cells, and that this signal transducing interaction leads to regulation of the functional activities of these cells. To test this hypothesis, we aim to examine; (i) the binding characteristics of mIgG to FcR on NK and the types of FcR involved in these interactions; (ii) the fate of mIgG after binding to NK cells; (iii) modulation of expression and function of FcgammaRIII induced by cytokines; (iv) analysis of the functional regulation of NK cells via FcR, by means of the synthetic peptide Y75. The long term goal of this research project is to better understand the interaction of NK cells bearing FcR with IgG in monomeric form, in view of the possible in vivo regulatory effects that circulating natural ligand may have in controlling the cytotoxic and non-cytotoxic functions of these effector cells.